The EU Commission has published a 193 page report that investigates the complex field of off-label use of medicines. The document examines the benefit risk balance of off-label use and the regulatory framework for such use.
Off-label is the term used to describe intentional use of a medicine that is outside of the terms of its marketing authorisation and approved product information (Summary of Product Characteristics [SmPC] and Patient Information Leaflet [PIL]), for example, use in an unapproved indication or patient population.
The general aim of the report was to provide a description of existing and proposed practices regarding off-label use of human medicines across EU Member States.
The specific objectives of the study were:
- Providing information on the prevalence and incidence of off-label use, and on its drivers;
- Providing information on the national frameworks, regulatory and other, governing the off-label use of medicinal products in various EU Member States. This includes describing how authorities have addressed the issue and the different ways patients, healthcare professionals and industry have reacted to this;
- Providing a factual analysis taking into account the EU legal framework for off-label use and practices in the EU Member States. This includes national legislation and case law. The study identifies particular aspects and/or therapeutic areas of off-label use that merit specific attention at the EU level.
The study used a wide range of data-gathering methods including a systematic review of scientific literature and grey literature, a legal analysis, interviews with stakeholders and an expert meeting.
Although EU legislation requires a marketing authorisation (MA) for a medicinal product, the legislation does not govern the way medicines are ultimately used in medical practice. The prescribing of a medicinal product, on-label or off-label, is a decision taken within the relationship between a patient and his or her treating doctor. The European Court of Justice confirmed that “off-label prescribing is not prohibited, or even regulated, by EU law” and that “There is no provision which prevents doctors from prescribing a medicinal product for therapeutic indications other than those for which a marketing authorisation has been granted.” (T-452/14 Laboratoires CTRS v Commission, paragraph 79). Off-label use is however, recognised as a concept by EU pharmaceutical law (recital 2 of Paediatric Regulation and pharmacovigilance provisions in Directive 2010/84/EU).
In the recent past, the EU has adopted the Paediatric Regulation (Regulation 1901/2006/EC) and the Orphan Medicinal Product (Regulation 141/2000/EC). In theory, both regulations could have a decreasing effect on off-label use, because more on-label options may become available. However, at the moment their exact effect on off-label use is unknown.
The extent of off-label use
Data from scientific literature showed that the prevalence of off-label use in the EU within the paediatric population is generally high, covers a broad range of therapeutic areas and is common practice for many prescribers in both the hospital and the outpatient settings. The situation was similar in the adult population. Variation in off-label prevalence was not only seen between but also within countries, depending for example on the methodology used and the population studied. A comparison of prevalence figures between the various EU Member States was therefore not possible, but it was apparent that the majority of, if not all, EU Member States are faced with off-label use of medicinal products to some extent.
Literature data reveals that off-label use in children and orphan diseases remains widespread. Clinical areas of interest regarding off-label use are oncology/haematology, psychiatry and rheumatology where there are unmet medical needs.
Drivers for off-label use
The report lists various drivers of off-label use.
The first of these concerns the limited incentives for the pharmaceutical industry to extend the labelling of existing medicinal products, especially for off-patent products. There is just one year of additional market protection if a new indication is registered in the first eight years after an MA has been granted provided the new indication confers significant clinical benefit over existing treatments. Perhaps this is an area the Commission should take another look at. When coupled with the increase in requirements for marketing authorisations as well as the sometimes long development times and high costs to investigate a new indication, it isn’t hard to see why companies often shy aware for MA extensions.
Another factor highlighted as a driver for off-label use was pricing and reimbursement. An important driver at patient and doctor level is the fact that there is sometimes no other choice than prescribing off-label. There can also be pressure from patients insisting on a particular medicine.
In many cases, it is probably not a single driver, but rather a combination of drivers that lead to off-label use.
Benefit risk of off-label use
Off-label use has advantages as well as disadvantages. A major advantage of off-label use is the better access of patients to (innovative) treatments and the fulfilment of medical needs of patients, especially in cases where no other options are available. Another positive element, mainly mentioned by regulators and policy makers in the field of reimbursement, was the potential economic advantage: off-label use contributes to sustainability of the healthcare system. The issue of liability in case of negative consequences of off-label use is a concern for many stakeholders from different backgrounds.
This study showed that the way Member States are deal with off-label use is not harmonised. Ten out of the 21 countries that participated in the study have specific policy tools in place for off-label use, e.g., the “temporary recommendations for use (RTU) scheme” in France and the Hungarian system where prescribers or their organisations have to ask for permission to prescribe a product off-label.
There are also measures to regulate reimbursement, for example, France and Italy explicitly allow for reimbursement of off-label use also when (on-label/authorized/not strictly identical) alternatives exist. There are policy tools providing guidance for prescribers such as the UK’s 2013 General Medical Council Guidance, which offers good practices in prescribing and managing medicines and devices. In the Netherlands off-label prescription is only allowed if the relevant professional body has developed protocols or professional standards with regard to that specific off-label use. Other policy tools are focused on the patient, for example, regarding the necessity for informed consent needed in many Member States or for serious interventions, upon request of the patient, a HCP has to register for what intervention the patient has given consent (also in The Netherlands).
In EU Member States without specific policy tools on off-label use, the general view is that off-label use is an issue to be dealt with at the level of the prescriber rather than at the regulatory or healthcare system level. However, a lack of clarity about the liability and patients being properly informed and providing consent remain a concern.
Moving forwards, there was a general consensus that a range of policy options at different levels is possible in the field of off-label use. So-called ‘soft approaches’, such as providing guidelines and collecting evidence in practice on off-label use, had the widest support among all stakeholders.
On the regulatory level, potential measures could include:
The possibility of using other evidence such as from monitoring patient cohorts, from routine patient registries and from reporting adverse events, rather than data from randomised controlled trials to support marketing authorisation extensions.
Providing guidance to Member States on off-label use, for example, by developing general advice on off-label use that provides direction for the development of national guidelines. This would also provide common ground for the development of national treatment guidelines in the individual EU Member States.
Improving the incentives for marketing authorisation holders to register new indications and other modalities (such as dosing, formulation) for existing products.
Click here to access the report.